Cancer patients undergoing treatment often experience a constellation of cancer treatment related symptoms (CTRS) which includes malaise, decreased appetite, sleep disturbance, difficulty thinking, anemia, pain, depressed mood and changes in body composition. These symptoms can greatly influence the subjective sensation of cancer treatment related fatigue (CTRF) which is the most common and distressing CTRS, and one that has a profoundly negative effect on physical functioning and QOL. Cancer patients often display a characteristic pattern of fatigue following treatment; peak fatigue occurring in the days following infusion but returning to baseline before the next chemotherapy cycle. Similar patterns of fatigue occur with each cycle. However, with continuing cycles fatigue levels often do not return to baseline resulting in persistent fatigue which can last for weeks, months and sometimes years after treatment has ended. CTRF can cause delays in treatment, dose reductions or termination of treatment, and has significant social and economic costs. There is also growing evidence that CTRF and its associated decline in physical activity can negatively impact body composition; increasing fat mass while decreasing lean and bone mass. This is of concern because these changes in body composition can impair physical functioning, increase the risk of bone fracture, cardiovascular disease, and cancer recurrence. Given the profound effects that CTRF has on QOL, physical functioning, and long term health, the treatment or prevention of this symptom is an essential component of cancer care. Because of the interrelationship between CTRS and CTRF, we must first understand the molecular mechanisms underlying the initiation and perpetuation of CTRS to effectively treat CTRF. We propose that CTRS/CTRF are initiated and perpetuated by treatment related production of inflammatory cytokines such as IL-12 and TNF-1. In this regard we propose that these symptoms are the same as sickness behavior a normal physiological response to harmful stimuli caused by increased production of IL-12 and TNF-1 peripherally and in the central nervous system. Our hypothesis is compatible with the emerging area of research on symptom clusters in cancer because we are exploring a potential mechanism for CTRS/ CTRF that may eventually explain the co-occurrence of fatigue, pain, depression, and other commonly experienced CTRSs. The goal of our program of research is to effectively prevent or decrease CTRS /CTRF thereby improving QOL, physical functioning and the long term health of cancer survivors. To effectively manage CTRS/CTRF we must first understand what causes them. In this proposal we describe an innovative bench to bedside approach to understanding the molecular origins of these symptoms. In this 5-year proposal we will complete the following study aims: 1) Determine whether acute symptoms in women undergoing cytotoxic chemotherapy for BC are associated with elevated serum levels of IL-12, TNF-1 and other inflammatory biomarkers, 2) Determine whether persistent CTRS/CTRF in women undergoing cytotoxic chemotherapy for BC is associated with evidence of CMV reactivation, 3) Determine the relationship between serum IL-6, IGF-1, changes in body composition and fatigue level in women undergoing treatment for BC, 4) Determine the role of inflammatory biomarkers in CTRS, cancer treatment efficacy and cancer recurrence. If successful, study findings could lead to the development of targeted therapies to prevent or treat CTRS/CTRF in cancer patients. PUBLIC HEALTH RELEVANCE: The impact that cancer treatment related symptoms (CTRS) has on quality of life and the patient's ability to receive the prescribed therapy makes the treatment of this symptom an essential component of cancer management. However, despite its prevalence, CTRF has been under-diagnosed, under-treated and under- researched. Clinicians have long suspected that inflammatory cytokines may play a role in CTRF, but to date the molecular mechanisms underlying the initiation and perpetuation of CTRF are not well established, and, the precise role of inflammatory cytokines, if any, in CTRF remains unclear. We will use a pre-clinical and clinical approach to examine the relationship between cancer treatment, inflammatory cytokines and CTRF. Understanding whether CTRF is initiated by the production of inflammatory cytokines may lead to new treatment strategies.